Dosace Form For Hormonal Contraceptive

ABSTRACT

A dosage form for hormonal contraception containing a given number of hormone-containing daily units and a given number of hormone-free daily units for daily, oral administration, where the hormone-containing daily units each contain at most the minimum effective daily amount of folic acid for women and the hormone-free daily units contain at least a multiple of this amount up to the maximum permissible amount of folic acid for women.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation in Part Application of U.S. patentapplication Ser. No. 11/009,817, still pending.

This application claims priority from German Patent Application No. 102004 026 671.9 filed May 28, 2004, German Patent Application No. 10 2004026 670.0 filed May 28, 2004, pending U.S. application Ser. No.11/009,817 and pending U.S. application Ser. No. 11/009,938.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a dosage form for hormonalcontraception containing a given number of hormone-containing dailyunits and a given number of hormone-free daily units for uninterrupteddaily oral administration to women, characterized in that thehormone-containing daily units contain folic acid in a daily amount ofat most 200 μg and the hormone-free daily units in each case containfolic acid in a daily amount of >200 μg up to the maximum permissibleamount of folic acid for women.

It is suspected that long-term taking of gestagen-based hormonalcontraceptives may lead to a deficiency of folic acid. This deficiencymay lead to cardiovascular diseases, for example.

It is also known that if pregnancy occurs a short time after stoppingtaking such hormonal contraceptives, there is a risk that the deficiencyof folic acid may lead to neural tube defects in the embryo. Since theneural tube develops in the first weeks of pregnancy, it is particularlyadvantageous to ensure that folic acid is taken prior to conception.

If, therefore, a woman stops taking hormonal contraceptives because shewants to have a child and she falls pregnant in the first cycle afterstopping the hormonal contraceptives, it is particularly important toensure an appropriately high level of folic acid in the period directlyafter stopping taking the “Pill”, as hormonal contraceptives are known.

There is therefore a need to add folic acid to hormonal contraceptivesin such a way that the added folic acid is adapted to a woman's varyingneeds over the period during and after a tablet-taking cycle.

2. Brief Description of Related Developments

The combination of hormonal contraceptives and folic acid is alreadyknown from WO 99/53910. The amount of folic acid per daily dose ofhormones merely matches the changes in a woman's folic acid requirementsas she ages, and does not take account of the changes in folic acidrequirements over a contraceptive-taking cycle.

SUMMARY OF THE INVENTION

It was therefore the object of the present invention to provide a dosageform for hormonal contraception which takes account of the changes infolic acid requirements during a hormone-taking cycle and subsequenthormone-free daily units.

This object was achieved by providing the dosage form according to theinvention for hormonal contraception containing a given number ofhormone-containing daily units and a given number of hormone-free dailyunits for uninterrupted daily oral administration to women,characterized in that the hormone-containing daily units contain folicacid in a daily amount of at most 200 μg and the hormone-free dailyunits in each case contain folic acid in a daily amount of >200 μg up tothe maximum permissible amount for women of folic acid.

Women of child-bearing age have a daily folic acid requirement which maybe adequately met by a healthy diet. Long term taking of hormonalcontraceptives containing gestagens may lead to an additional folic acidrequirement, which may likewise be met by a healthy diet. However, it isadvisable to provide women with a daily dose of the minimum effectivedaily amount of folic acid.

Accordingly, hormone-containing daily units of the dosage form accordingto the invention may each comprise a daily amount of folic acidcorresponding to this minimum effective daily amount of folic acid.Preferably, the hormone-containing daily units of the dosage formaccording to the invention contain 0 to 200 μg of folic acid,particularly preferably 5 to 200 μg of folic acid.

The hormone-containing daily units of the dosage form according to theinvention may also not contain any additional folic acid, however.

To ensure that a woman consumes the necessary amount of folic acid orthat her increased folic acid requirement at least at the beginning ofpregnancy is met as quickly as possible if she decides to try for ababy, so avoiding possible damage to the embryo due to a folic aciddeficiency, the hormone-free daily units of the folic acid dosage formaccording to the invention contain folic in an amount of more that 200μg up to the maximum permissible daily amount of folic acid for women,preferably up to 5 mg of folic acid per daily unit, particularlypreferably of more than 200 μg to 5 mg folic acid, very particularlypreferably up to the maximum permissible daily amount of folic add forwomen of reproductive age.

By adding folic acid to the hormone-free daily units of the dosage formaccording to the invention in amounts of up to the maximum permissibleamount, it is possible to increase the folic acid concentration in awoman's body while she is taking the hormone-free daily units to theextent that the her body's increased folic acid requirement is met asquickly as possible if she stops taking a hormone-containingcontraceptive and then falls pregnant.

The hormone-containing daily units of the dosage form according to theinvention preferably each contain the same amount of folic acid. Thisalso applies to the hormone-free daily units, which likewise eachcontain the same amount of folic acid, this being greater than theamount contained in the hormone-containing daily units however.

The folic acid may also be present in the dosage form according to theinvention as a pharmaceutically safe salt, preferably as sodium,potassium or magnesium salt, or as a corresponding derivative.

Suitable derivatives of folic acid are mono- or diesters, wherein thediesters may be differently or identically esterified. Suitable estergroups are preferably C₁-C₈ low alkyl groups, such as methyl, ethyl,propyl or butyl, branched C₁-C₈ low alkyl groups, such as isopropyl,isobutyl or sec.-butyl, cycloalkyl groups, such as cyclopentyl orcyclohexyl, aryl groups, such as phenyl or substituted phenyl with 1-2substituents, such as low alkyl or haloalkoxyl groups, or arylalkylgroups with C₁-C₈ alkyl and aryl groups, such as phenyl or substitutedphenyl.

In addition, the hormone-free daily units and optionally thehormone-containing daily units may contain further vitamins or mineralsin addition to the folic acid.

The number of daily units of a dosage form according to the inventionmay correspond to a natural, monthly menstrual cycle. In this case, thedosage form according to the invention contains 21 to 25hormone-containing daily units and 7 to 3 hormone-free daily units.

However, it is also possible for the total number of hormone-containingdaily units to correspond to more than a woman's natural monthly cycle,such that a dosage form according to the invention may containhormone-containing daily units to be taken without interruption for upto 2 years, preferably up to 1 year, and 7 to 3 hormone-free dailyunits. However, it is also possible for the dosage form according to theinvention to comprise 42 to 52 or 77 to 193 hormone-containing dailyunits alongside 7 to 3 hormone-free daily units.

The hormone-containing daily units of the dosage form according to theinvention may each contain at least one contraceptively acting hormonecomponent, preferably a combination of hormone components such as anoestrogen and a gestagen.

Oestrogens which are suitable for the hormone-containing daily units ofthe dosage form according to the invention are preferably selected fromthe group comprising oestradiol, oestradiol valerate, ethinyloestradioland mestranol. Ethinyloestradiol is particularly preferred as theoestrogen for the dosage form according to the invention.

Gestagens which are suitable for the hormone-containing daily units ofthe dosage form according to the invention are preferably selected fromthe group comprising norethisterone, norethisterone acetate,norethisterone enantate, norgestimate, norgestrel, levonorgestrel,gestodene, hydroxyprogesterone caproate, medroxyprogesterone acetate,megestrol acetate, chlormadinone acetate, lynestrenol, cyproteroneacetate, drospirenone, dienogest, desogestrel, progesterone,dydrogesterone, medrogestone, ethynodiol, promegestone, nomegestrolacetate and trimegestone.

The hormones are preferably used in the amounts stated below.

Oestrogens: Oestradiol, oestradiol valerate 0.5 to 4 mgEthinyloestradiol 5 to 50 μg Mestranol 8 to 70 μg

Gestagens: Norethisterone, norethisterone acetate 0.5 to 1.0 mgNorgestimate 0.1 to 0.25 mg Norgestrel 0.3 to 1.0 mg Levonorgestrel 0.05to 0.15 mg Gestodene 0.05 to 0.12 mg Hydroxyprogesterone caproate 10 to800 mg Medroxyprogesterone acetate 2.5 to 40 mg Megestrol acetate 1.0 to10 mg Chlormadinone acetate 0.5 to 10 mg Lynestrenol 0.4 to 3 mgCyproterone acetate 0.5 to 10 mg Drospirenone 1.0 to 10 mg Dienogest 1.0to 10 mg Desogestrel 0.06 to 0.30 mg Progesterone 100 to 1000 mgDydrogesterone 5 to 50 mg Medrogestone 2 to 30 mg Ethynodiol, ethynodioldiacetate 0.4 to 3 mg Promegestone 0.5 to 10 mg Nomegestrol acetate 0.5to 10 mg Trimegestone 1 to 10 mg Etonogestrel 0.1 to 1 mg Norelgestromin0.1 to 2 mg Norethynodrel 0.3 to 3 mg Tibolone 1 to 10 mg

The dosage forms according to the invention, especially thehormone-containing daily units, preferably comprise the followinghormone combinations:

1. 0.015 mg ethinyloestradiol+0.06 mg gestodene2. 0.02 mg ethinyloestradiol+0.15 mg desogestrel3. 0.02 mg ethinyloestradiol+0.5 mg norethisterone4. 0.02 mg ethinyloestradiol+1 mg chlormadinone acetate or 2 mg or 3 mgchlormadinone acetate5. 0.02 mg ethinyloestradiol+1 mg norethisterone6. 0.03 mg ethinyloestradiol+1 mg norethisterone7. 0.02 mg ethinyloestradiol+4 mg chlormadinone acetate8. 0.02 mg ethinyloestradiol+5 mg chlormadinone acetate9. 0.02 mg ethinyloestradiol+0.1 mg levonorgestrel10. 0.02 mg ethinyloestradiol+0.15 mg desogestrel11. 0.02 mg ethinyloestradiol+0.1 mg levonorgestrel12. 0.03 mg ethinyloestradiol+3 mg drospirenone13. 0.02 mg ethinyloestradiol+3 mg drospirenone14. 0.03 mg ethinyloestradiol+2 mg chlormadinone acetate15. 0.035 mg ethinyloestradiol+0.25 mg norgestimate16. 0.03 mg ethinyloestradiol+0.5 mg norethisterone17. 0.03 mg ethinyloestradiol+0.15 mg desogestrel18. 0.03 mg ethinyloestradiol+0.075 mg gestodene19. 0.03 mg ethinyloestradiol+0.15 mg levonorgestrel20. 0.03 mg ethinyloestradiol+0.15 mg desogestrel21. 0.03 mg ethinyloestradiol+0.15 mg levonorgestrel22. 0.03 mg ethinyloestradiol+0.125 mg levonorgestrel23. 0.0375 mg ethinyloestradiol+0.75 mg lynestrenol24. 0.03 mg ethinyloestradiol+1 mg norethisterone25. 0.03 mg ethinyloestradiol+0.5 mg norethisterone26. 0.03 mg ethinyloestradiol+0.15 mg levonorgestrel27. 0.04 mg ethinyloestradiol+2 mg lynestrenol28. 1st phase=7 days

-   -   0.050 mg desogestrel+0.035 ethinyloestradiol    -   2nd phase=7 days    -   0.100 mg desogestrel+0.030 ethinyloestradiol    -   3rd phase=7 days    -   0.150 mg desogestrel+0.030 ethinyloestradiol        29. 1st phase=6 days    -   0.03 mg EE+0.05 mg levonorgestrel    -   2nd phase=5 days    -   0.04 mg EE+0.075 mg levonorgestrel    -   3rd phase=10 days    -   0.03 mg EE+0.125 mg levonorgestrel        30. 1st phase=7 days    -   0.035 mg EE+0.180 mg norgestimate    -   2nd phase=7 days    -   0.035 mg EE+0.215 mg norgestimate    -   3rd phase=7 days    -   0.035 mg EE+0.250 mg norgestimate        31. 1st phase=6 days    -   0.03 mg EE+0.05 mg levonorgestrel    -   2nd phase=5 days    -   0.04 mg EE+0.075 mg levonorgestrel    -   3rd phase=10 days    -   0.03 mg EE+0.125 mg levonorgestrel        32. 1st phase=7 days    -   0.035 mg EE+0.5 mg norethisterone    -   2nd phase=9 days    -   0.035 mg EE+1 mg norethisterone    -   3rd phase=5 days    -   0.035 mg EE+0.5 mg norethisterone        33. 1st phase=6 days    -   0.03 mg EE+0.05 mg levonorgestrel    -   2nd phase=5 days    -   0.04 mg EE+0.075 mg levonorgestrel    -   3rd phase=10 days    -   0.03 mg EE+0.125 mg levonorgestrel        34. 1st phase=7 days    -   0.035 mg-EE+0.5 mg norethisterone    -   2nd phase=7 days    -   0.035 mg EE+0.75 mg norethisterone    -   3rd phase=7 days    -   0.035 mg EE+1 mg norethisterone        35. 1st phase=6 days    -   0.03 mg EE+0.05 mg levonorgestrel    -   2nd chase=5 days    -   0.04 mg EE+0.075 mg levonorgestrel    -   3rd phase=10 days    -   0.03 mg EE+0.125 mg levonorgestrel        36. 1st phase=6 days    -   0.03 mg EE+0.05 mg levonorgestrel    -   2nd phase=6 days    -   0.04 mg EE+0.075 mg levonorgestrel    -   3rd phase=9 days    -   0.03 mg EE+0.125 mg levonorgestrel        37. 1st phase=6 days    -   0.03 mg EE+0.05 mg levonorgestrel    -   2nd phase=5 days    -   0.05 mg EE+0.05 mg levonorgestrel    -   3rd phase=10 days    -   0.04 mg EE+0.125 mg levonorgestrel        38. 1st phase=6 days    -   0.03 mg EE+0.05 mg levonorgestrel    -   2nd phase=5 days    -   0.04 mg EE+0.075 mg levonorgestrel    -   3rd phase=10 days    -   0.03 mg EE+0.125 mg levonorgestrel        39. 0.035 mg ethinyloestradiol+2 mg cyproterone acetate        40. 0.05 mg mestranol+2 mg chlormadinone acetate        41. 1st phase=11 days    -   0.05 mg ethinyloestradiol+1 mg chlormadinone acetate    -   2nd phase=11 days    -   0.05 mg ethinyloestradiol+2 mg chlormadinone acetate        42. 0.08 mg mestranol+2 mg chlormadinone acetate        43. 0.03 mg ethinyloestradiol+2 mg dienogest        44. 0.05 mg ethinyloestradiol+0.5 mg norgestrel        45. 0.05 mg ethinyloestradiol+0.125 mg levonorgestrel        46. 0.05 mg ethinyloestradiol+0.25 mg levonorgestrel        47. 0.05 mg ethinyloestradiol+0.125 mg levonorgestrel        48. 0.05 mg ethinyloestradiol+1 mg norethisterone acetate        49. 0.05 mg ethinyloestradiol+0.25 mg levonorgestrel        50. 1st phase=7 days    -   0.04 mg ethinyloestradiol+0.025 mg desogestrel    -   2nd phase=15 days    -   0.03 mg ethinyloestradiol+0.125 mg desogestrel        51. 1st phase=11 days    -   0.05 mg ethinyloestradiol+0.05 mg levonorgestrel    -   2nd phase=10 days    -   0.05 mg ethinyloestradiol+0.125 mg levonorgestrel        52. 1st phase=11 days    -   0.05 mg ethinyloestradiol+0.05 mg levonorgestrel    -   2nd phase=10 days    -   0.05 mg ethinyloestradiol+0.125 mg levonorgestrel        53. 1st phase=7 days    -   0.05 mg ethinyloestradiol+    -   2nd phase=15 days    -   0.05 mg ethinyloestradiol+2.5 mg lynestrenol        54. 1st phase=7 days    -   0.05 mg ethinyloestradiol+    -   2nd phase=15 days    -   0.05 mg ethinyloestradiol+0.125 mg desogestrel        55. 1st phase=6 days    -   0.05 mg ethinyloestradiol+    -   2nd phase=15 days    -   0.05 mg ethinyloestradiol+1 mg norethisterone acetate

Where the dosage form according to the invention provides a multiphasichormone combination, it is recommended that the hormone-containing dailyunits be taken without interruption only for a period of 21 to 25 days,followed by 7 to 3 days of taking hormone-free daily units.

The dosage form according to the invention preferably comprises at least21, preferably 21 to 25, hormone-containing daily units which preferablyinclude 5 to 30 μg of ethinyloestradiol and 0.5 to 5 mg of chlormadinoneacetate, and 3 to 7 hormone-free daily units. However, the dosage formaccording to the invention may also comprise hormone-containing dailyunits for several years, preferably of 42 to 365 units, which containthe stated hormone combination in the stated ranges, wherein thecorresponding uninterrupted tablet-taking periods are followed by 7 to 3hormone-free daily units with an elevated amount of folic acid statedaccording to the invention.

As already stated, the hormone-containing daily units of the dosage formaccording to the invention may take the form of a monophasic (one-phase)or multiphasic contraceptive. In the case of a multiphasiccontraceptive, a two-phase or a three-phase pill may be present, whichis not usually suitable, however, to be taken for a period longer than awoman's natural cycle.

The dosage form according to the invention may also be a constituent ofa kit, wherein the kit according to the invention may comprise aplurality of the dosage forms according to the invention, especially ifone dosage form comprises only one monthly cycle.

The kit may optionally include a calendar or a diary.

EXAMPLES Example 1 a) Composition

Per tablet Ethinyloestradiol  0.020 mg Chlormadinone acetate  2.000 mgPovidone K30  3.000 mg Lactose 31.980 mg Maize starch 12.000 mgMagnesium stearate  0.500 mg Highly disperse silicon dioxide  0.500 mg

Ethinyloestradiol (EE) and povidone K30 (polyvinylpyrrolidone) weredissolved in 600 ml of ethanol. Chlormadinone acetate (particle size90%<50 μm), lactose and maize starch were mixed in a mixer/pelletiser(Diosna P25) for 5 mins. and then moistened thoroughly and mixed withthe ethanolic EE/PVP solution. The moist composition was forced througha 3 mm screen and dried in a vacuum drying cabinet. The dried granularproduct was disagglomerated through a 0.6 mm screen, mixed withmagnesium stearate and highly disperse silicon dioxide and pressed on atablet press with 5 mm punches into tablets with a weight of 50 mg.

b) As indicated under a), hormone-free, folic acid-containing tabletswith a weight of 50 mg were produced, wherein the sodium salt of thefolic acid was dissolved in 600 ml of aqueous ethanol.

Per tablet Sodium folate  3.000 mg Povidone K30  3.000 mg Lactose 31.000mg Maize starch 12.000 mg Magnesium stearate  0.500 mg Highly dispersesilicon dioxide  0.500 mg

The tablets were coated with a methylhydroxypropylcellulose-basedcoating (e.g. Opadry YS-1-2184 made by Colorcon), coating composition 2mg per tablet, and packaged into a dosage form comprising 120hormone-containing daily units without folic acid and 7 hormone-freedaily units with folic acid.

1-15. (canceled)
 16. A hormonal contraceptive dosage form foruninterrupted daily oral administration to women, said dosage formcomprising hormone-containing daily units and hormone-free daily units,wherein each of the hormone-containing daily units does not comprise anyfolic acid and each of the hormone-free daily units comprises folic acidin a daily amount of >200 μg up to the maximum permissible amount offolic acid for women.
 17. A dosage form according to claim 16, whereinthe hormone-free daily units each comprises more than 200 μg and up to 5mg of folic acid.
 18. A dosage form according to claim 16, wherein thehormone-free daily units each comprises the same amount of folic acid.19. A dosage form according to claim 16, wherein the dosage formcomprises at least 21 hormone-containing daily units and 7 to 3hormone-free daily units.
 20. A dosage form according to claim 19,wherein the number of hormone-containing daily units is sufficient foradministration for a maximum of 2 years, and the number of hormone-freedaily units is sufficient for administration for 7 to 3 days.
 21. Adosage form according to claim 19, comprising up to730-hormone-containing daily units and 7 to 3 hormone-free daily units.22. A dosage form according to claim 19, which comprises 21 to 25hormone-containing daily units and 7 to 3 hormone-free daily units. 23.A dosage form according to claim 19, which comprises 42 to 52hormone-containing daily units and 7 to 3 hormone-free daily units. 24.A dosage form according to claim 19, which comprises 77 to 193hormone-containing daily units and 7 to 3 hormone-free daily units. 25.A dosage form according to claim 19, wherein the dosage form comprisesup to 365 hormone-containing daily units and 7 to 3 hormone-free dailyunits.
 26. A dosage form according to claim 16, wherein thehormone-containing daily units each comprises at least one contraceptiveactive hormone component.
 27. A dosage form according to claim 26,wherein the hormone-containing daily units each comprises ahormone-combination consisting of an oestrogen and a gestagen.
 28. Adosage form according to claim 16, wherein the hormone-containing dailyunits correspond to a monophasic contraceptive.
 29. A kit comprising atleast one dosage form for hormonal contraception according to claim 16.30. A kit form according to claim 29, wherein the kit comprises aplurality of dosage forms for hormonal contraception according to claim16.